White matter-associated striatal astrocytes and their role in apathy in Huntington's disease

PROJECT SUMMARY Huntington’s disease (HD) is a neurodegenerative disease that primarily affects the striatum, a brain region that controls movement and some forms of cognition. Patients manifest a myriad of motor, cognitive, and neuropsychiatric symptoms, the latter being the most burdensome. Apathy is the most prevalent neuropsychiatric symptom in HD and is strongly associated with cognitive dysfunction and suicide, which is the third most common cause of death in HD. The treatment of apathy should be a priority in the clinical care of HD patients, but the etiology or pathophysiology of apathy in HD is unknown. The goal of this proposal is to fill this gap in knowledge and provide insights into the cellular mechanisms that regulate apathy in HD. This is crucial to develop effective treatments to prevent unnecessary deaths and improve the quality of life of HD patients. Studies in the general population have shown that systemic inflammation and white matter (WM) lesions are risk factors for apathy. Increased inflammation and WM atrophy are found in the striatum of patients and mouse models of HD and we and others have shown that dysfunction of striatal astrocytes in HD plays a critical role in these processes. Astrocyte dysfunction has previously been associated with mood disorders, but whether striatal astrocytes regulate apathy in HD is unknown. We recently showed that a subpopulation of striatal reactive astrocytes expressing the glial fibrillary acidic protein (GFAP+), but not other known astrocyte markers, are clustered around a subset of axon bundles (WM fascicles) traversing the dorsomedial striatum (DMS) of a mouse model of HD (zQ175), a phenomenon that increased with disease severity. The DMS along with regions of the medial prefrontal cortex (mPFC) are interconnected and regulate motivation-related behaviors such as apathy. Based on this evidence we hypothesize that a specialized population of GFAP+ astrocytes accumulate on WM fascicles derived from the mPFC and traversing the DMS in HD, causing WM atrophy and apathy related behaviors. To test this hypothesis, we will conduct three complementary aims: Aim 1) we will identify the origin of WM fascicles associated with GFAP+ astrocytes in the DMS of HD mice using anterograde viral tracing analyses from injections conducted in different cortical regions and GFAP immunostaining analyses, Aim 2) we will characterize the astrocytes associated with WM in the DMS of HD mice using coupled spatial transcriptomics and proteomic analyses using the Nanostring nCounter system, and Aim 3) elucidate the effect of ablating WM associated striatal astrocytes in the regulation of WM atrophy and apathy by using an astrocyte selective viral expression of the diphtheria toxin fragment A in the DMS of HD mice. Successful completion of this proposal may reveal a new mechanistic connection between WM atrophy, striatal gliosis, and apathy in HD and will serve the basis for future functional characterization analyses of WM-associated astrocytes to start uncovering new ways to treat neuropsychiatric symptoms in HD.